Pediatric Polycythemia

Updated: Jun 02, 2020
Author: May C Chien, MD; Chief Editor: Max J Coppes, MD, PhD, MBA 


Practice Essentials

Polycythemia refers to increased red blood cell mass and is often used interchangeably with the term erythrocytosis. 

Polycythemia can be primary or secondary.  Primary polycythemias are caused by inherited or acquired mutations resulting in dysregulated erythroid development, whereas secondary polycythemias are caused by increased erythropoiesis-stimulating factors. Relative polycythemia, or pseudoerythrocytosis, is caused by an apparent red blood cell mass increase due to plasma volume reduction (eg, due to severe diarrhea with subsequent dehydration), resulting in increased hemoconcentration. 

This article will review both primary and secondary polycythemias. A specific type of primary polycythemia, polycythemia rubra vera (often just called polycythemia vera) is an acquired myeloproliferative disorder which is discussed in detail elsewhere (Pediatric Polycythemia Vera). 

Laboratory Definitions

The following laboratory terms are used to document polycythemia.


The hematocrit (Hct) is the percentage of blood that red blood cells occupy. An adult patient with an Hct of over 48% (in women) or more than 52% (in men) is considered to be polycythemic. In pediatric patients, the Hct must be corrected for age, including gestational age for neonates.[1]

Hemoglobin concentration

The protein hemoglobin, found in red blood cells, is responsible for oxygen delivery. An adult patient in whom the hemoglobin concentration (Hgb) is above 16.5 g/dL (in women) or over 18.5 g/dL (in men) is considered to be polycythemic. In children, the Hgb, like the Hct, must be corrected for age.

Symptoms of polycythemia

These include the following:

  • Headache, dizziness, vertigo
  • Weakness, malaise, or myalgias
  • Visual disturbances
  • Tinnitus
  • Diaphoresis
  • Pruritus - Especially after exposure to warm water
  • Erythromelalgia - Burning pain, warmth, and redness of extremities
  • Dyspnea
  • Arthropathies
  • Epigastric discomfort, satiety, constipation, weight loss
  • Chest pain

Workup in polycythemia

The following laboratory findings can be seen in polycythemia:

  • Complete blood count (CBC) - Leukocytosis and thrombocytosis are commonly observed but not universal in patients with polycythemia; large platelets are often seen; red cell mass is greater than 36 mL/kg in men and greater than 32 mL/kg in women
  • Serum erythropoietin (Epo) - Elevated serum Epo levels can be used to distinguish polycythemia vera (PV) from secondary polycythemia
  • Elevated sedimentation rate
  • Spurious hyperkalemia or hypokalemia
  • Increased blood viscosity
  • Artifactual prolongation of coagulation studies

Management of polycythemia

Treatments for primary polycythemia include the following:

  • Phlebotomy - The goal of phlebotomy is to maintain normal red cell mass and blood volume, with a target hematocrit level of 42-46% for men and 39-42% for women
  • Hydroxyurea - Hydroxyurea as a myelosuppressive agent is also widely used in high-risk patients with polycythemia vera (ie, >60 y, history of thrombosis) who require cytoreductive therapy, reducing the need for phlebotomy [2]
  • Interferon - Interferon-alpha is effective in eliminating JAK2V617Fexpression and inducing hematologic remission
  • Tyrosine kinase inhibitors

Phlebotomy is used for symptomatic hyperviscosity in secondary polycythemia.


Normal Red Blood Cell Development

Red cell development, or erythropoiesis, is a carefully ordered sequence of events. This process initially occurs in fetal liver cells and subsequently takes place in the bone marrow of children and adults. Normal erythropoiesis begins with multipotent hematopoietic stem cells, which differentiate into erythroid progenitors, eventually to develop into the mature red blood cells. The hormone erythropoietin (Epo) is essential to this process. In the fetus, Epo is produced by monocytes and macrophages found in the liver. After birth, the majority of Epo is produced in the kidneys. The major stimulus for Epo production is hypoxia. Anemia, decreased hemoglobin oxygen saturation, decreased oxygen release from hemoglobin, and reduced oxygen delivery can all be sensed in the kidney and lead to the increased production of Epo. Erythropoiesis is carefully regulated with negative feedback inhibition from increased oxygen delivery, which down-regulates Epo production.  

Upon Epo binding to its receptor, EpoR, signaling through the Janus kinase 2 (JAK2) pathway activates multiple signaling cascades, leading to reduced cell death and expansion and differentiation of progenitor cells to mature red blood cells. The hypoxia-inducible factor (HIF) pathway regulates a cascade of genes allowing survival in low-oxygen conditions. The transcription factor HIF consists of two subunits, α and β. The α subunit becomes stabilized in low-oxygen conditions, translocates to the nucleus, and dimerizes with the β subunit to promote gene transcription. In oxygen sufficient environments, HIF is degraded by the von Hippel-Lindau (VHL) tumor suppressor complex.[3]

Primary Polycythemia

Primary polycythemias are due to factors intrinsic to red cell precursors caused by acquired or inherited mutations. These polycythemias include the diagnoses of polycythemia vera and primary familial and congenital polycythemia.  

Primary familial and congenital polycythemia (PFCP) is caused by germline mutations in the EpoR leading to constitutive activation of EpoR. The constantly activated "on switch" leads to excessive erythroid progenitor proliferation and differentiation, resulting in polycythemia. This autosomal dominant trait does not necessarily carry an adverse prognosis early in life but is associated with an increased risk of thrombotic and vascular mortality later in life.[4]   

Polycythemia vera is caused by an acquired gain-of-function mutation of JAK2 tyrosine kinase. The JAK2V617F mutation is detectable in more than 95% of patients diagnosed with polycythemia vera.[5] Several other mutations of JAK2 have since been described (eg, exon 12, JAK2H538-K539delinsI).[6, 7] The JAK2 mutations cause the enzyme to be constitutively active, allowing these cells to be hypersensitive to Epo.[5]

Chuvash polycythemia, a congenital polycythemia first recognized in an endemic Russian population, is a variant of primary familial and congenital polycythemia. It results from a mutation in the von Hippel-Lindau (VHL) gene, a negative regulator of erythropoiesis, resulting in impaired ability of VHL to down-regulate Epo and erythropoiesis.[4]

Secondary Polycythemia

Secondary polycythemia is due to circulating extrinsic factors that stimulate erythropoiesis, most often Epo. Physiologic elevation of Epo may result from functional hypoxia secondary to pulmonary, cardiac, renal, or hepatic disease. Polycythemia can also develop owing to Epo-secreting tumors, including renal cell carcinomas, nephroblastomas, and endocrine tumors.

High-altitude erythrocytosis is evident within the first week of high-altitude exposure. A sharp increase in Epo production is noticeable, with associated mobilization of iron stores with evidence of iron-deficient erythropoiesis.[4]

Abnormal high-affinity hemoglobin mutations are characterized by left shift in the oxygen-hemoglobin dissociation curves. The resulting tissue hypoxia stimulates Epo production, leading to erythrocytosis. Similarly, in familial polycythemia with defects in 2,3-DPG metabolism, a left shift in the oxygen-hemoglobin curve is noted with a physiologic response of polycythemia.[4]

Secondary polycythemia of the newborn is fairly common and is seen in 1-5% of all newborns in the United States. It results from either chronic or acute fetal hypoxia or from delayed cord clamping and stripping of the umbilical cord.[8]


The clinical manifestations of polycythemia stem from increased red cell mass, which leads to increased blood viscosity. Blood viscosity increases logarithmically with increases in hematocrit, resulting in impaired blood flow and increased cardiac workload.

In the neonatal period, polycythemia-induced hyperviscosity can lead to altered blood flow and can subsequently affect organ function. Infants with polycythemia are at increased risk for necrotizing enterocolitis, renal dysfunction, hypoglycemia, and increased pulmonary vascular resistance with resultant hypoxia and cyanosis. However, a study by Hopfeld-Fogel et al, involving 119 term infants with polycythemia and 117 controls, did not find neonatal hypoglycemia to be more common in the presence of neonatal polycythemia. The investigators suggested that when the two conditions do occur together neonatally, this represents the effect of common risk factors.[9]

Although initially thought to cause neurologic dysfunction, the decrease in cerebral blood flow seen in newborns with polycythemia is a physiologic response and does not appear to cause cerebral ischemia.[8]


The incidence, morbidity, and mortality of polycythemia depends on the underlying etiology, varying greatly. The epidemiology specifically of polycythemia vera has been studied extensively and is reviewed below.


United States

Primary polycythemia is rare; in the United States, the overall prevalence of polycythemia vera is 45-57 cases per 100,000 people.[10, 11] The combined annual incidence is 0.01-2.61 per 100,000 people.[12] The median age is 60 years, with 0.01% of those cases observed in individuals younger than 20 years.[13] Less than 50 cases of pediatric polycythemia vera have been reported in the literature. Polycythemia vera is less likely in blacks than in individuals of European ancestry, with a higher incidence in Ashkenazi Jews.


Polycythemia vera has a similar incidence in Western Europe as in the United States, and occurrence rates are very low in Africa and Asia (as low as 2 cases per million per year in Japan).

Mortality and Morbidity

Death rates for children are unavailable. The complications found in polycythemia vera are related to two primary factors. The first includes complications related to hyperviscosity. The second involves bone marrow–related complications. Untreated, the median survival time for these patients is 18 months. However, if patients are treated, survival is greatly extended, as many as 10-15 years with phlebotomy alone. The causes of death in adults are as follows:

  • Thrombosis/thromboembolism (30-40%) - Myocardial infarctions, deep vein thrombosis, pulmonary embolus, portal splenic and mesenteric vein thrombosis
  • Other malignancies (15%)
  • Hemorrhage (2-10%)
  • Myelofibrosis/myeloid metaplasia (4%)
  • Other (25%)


In the United States, higher rates of polycythemia vera are observed in the Ashkenazi Jewish population, and lower rates are seen in blacks.


Polycythemia vera is somewhat more common in males, with the male-to-female ratios in several studies, ranging from 1.2-2.2. In children, it appears to affect males and females equally.[4]


The median age for polycythemia vera between age 60-80 years.[4, 13] Less than 1% of polycythemia cases occur in people younger than 20 years.




The clinical features associated with polycythemia are a direct result of the increase in red cell mass, which causes an expansion of blood volume. Signs of hyperviscosity and increased metabolism accompany polycythemia. A thorough history must be obtained for a history of cardiac, pulmonary (including sleep apnea), hepatic or renal disease in the patient and a complete family history for evidence of familial polycythemia.[14, 15]

Symptoms include the following:

  • Headache, dizziness, vertigo
  • Weakness, malaise, or myalgias
  • Visual disturbances
  • Tinnitus
  • Diaphoresis
  • Pruritus (especially after exposure to warm water)
  • Erythromelalgia (burning pain, warmth, and redness of extremities)
  • Dyspnea
  • Arthropathies
  • Epigastric discomfort, satiety, constipation, weight loss
  • Chest pain

Symptoms especially suggestive of polycythemia vera include postbath pruritus, erythromelalgia (burning pain and erythema of the hands and feet), gout, thromboses, and bleeding.


A thorough physical examination must be completed and include specific evaluation for signs and symptoms of underlying disease that may cause secondary polycythemia; it must include pulse oximetry, careful cardiac and pulmonary evaluation, and evaluation for signs of renal or hepatic disease.[4]

Signs and symptoms of polycythemia are attributed to the expanded total blood volume and resultant slowing of blood flow. Clinical findings of polycythemia include the following (frequency in parentheses):

  • Splenomegaly (70%)
  • Skin plethora (67%)
  • Conjunctival plethora (59%)
  • Hepatomegaly (40%)
  • Systolic blood pressure >140 mm Hg (72%)
  • Diastolic blood pressure >90 mm Hg (32%)

Evaluating neonates with polycythemia, Vlug et al found thrombocytopenia in 51% (71 out of 140) of these patients and severe thrombocytopenia in 9% (13 out of 140) of them. The investigators also determined, through multiple regression analysis, that thrombocytopenia was independently associated with small size for gestational age. In addition, a negative correlation was found between platelet count and hematocrit.[16]


Primary polycythemia

Causes include the following:

  • Polycythemia vera
  • Primary familial and congenital polycythemia (PFCP)                                                                    
  • Chuvash polycythemia
  • Rare mutations resulting in disordered hypoxia sensing (prolyl hydroxylase 2 [PHD2], HIF2α)

Polycythemia vera

Polycythemia vera is considered to be a form of the myeloproliferative syndromes that also include essential thrombocythemia and primary myelofibrosis. The clonality of polycythemia vera is well established and was first demonstrated by Adamson et al in 1976.[17]  Subsequent studies suggest hypersensitivity of the myeloid progenitor cells to growth factors, including Epo, interleukin (IL)–3, stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and insulin-like growth factor (IGF)–1, whereas other studies show defects in programmed cell death.

In 2004, several groups identified a gain-of-function mutation in the gene that encodes for the JAK2 tyrosine kinase that leads to constitutive phosphorylation and therefore constitutive activity and STAT recruitment[18, 19, 20, 21, 22]  The JAK2 V617F mutation is a point mutation that causes a substitution of phenylalanine for valine in exon 14. JAK2V617F is detectable in more than 95% of patients diagnosed with polycythemia vera.[5]  Several other mutations of JAK2 have since been described (eg, exon 12, JAK2H538-K539delinsI).[6, 7, 23, 24]  The JAK2 mutations result in the enzyme being constitutively active, allowing cytokine-independent proliferation of cell lines that express Epo receptors, causing these cells to be hypersensitive to cytokines.[5]

Familial clustering suggests a genetic predisposition. Whether these mutations are responsible for the development of polycythemia vera in pediatric patients is unclear. Some groups have reported lower rates of JAK2 mutations in children compared with adults,[25, 26, 27]  whereas other groups have seen similar rates, with complete or near complete presence of JAK2V617Fand other JAK2 mutations.[7] . The prevalence of familial cases of chronic myeloproliferative disease is thought to be at least 7.6%, and the pattern of inheritance is consistent with an autosomal dominant pattern with decreased penetrance. Evidence of disease anticipation is noted in the second generation, presenting at a significantly younger age. However, clinical and hematologic features in familial cases have not been shown to differ from those of sporadic mutations.[28]

Currently, the diagnosis of polycythemia vera is based on the 2016 World Health Organization (WHO) criteria, which have integrated molecular diagnostics into the evaluation and screening for polycythemia vera.[29, 30, 31]  A diagnosis of polycythemia vera is made when all three major criteria are present or when the first two major criteria and a minor criterion are present.

The major criteria are as follows:

  • Increased Hgb (>16.5 g/dL in men or >16.0 g/dL in women) or Hct (>49% in men or >48% in women) or other evidence of increased red cell volume
  • Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis), including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size)
  • JAK2V617F or  JAK2 exon 12 mutation

The minor criterion is as follows:

  • Serum erythropoietin level below the reference range for normal

The second major criterion may not be required if there is sustained absolute erythrocytosis (Hgb >18.5 g/dL or Hct >55.5%, in men; Hgb >16.5 g/dL or Hct >49.5%, in women) and the third major criterion and the minor criterion are present.

Primary familial and congenital polycythemia (PFCP)

Patients with PFCP are commonly found to have mutations in the EPOR gene, the gene that codes for the erythropoietin receptor. Approximately 14 mutations have been identified. Unlike patients with polycythemia vera, patients with PFCP lack splenomegaly, neutrophilia, basophilia, thrombocytosis, and a JAK2 mutation. PFCP is generally thought to be benign, but it carries an increased risk of cardiovascular disease.

Chuvash polycythemia

Chuvash polycythemia, a congenital polycythemia first recognized in an endemic Russian population, is caused by a mutation in the von Hippel-Lindau (VHL) gene resulting in a perturbed oxygen-dependent regulation of Epo synthesis. Clinically, these patients have increased incidence of thrombosis, elevated pulmonary pressures, and an increased mortality independent of the increase in Hct.

Several mutations in addition to Chuvash polycythemia have been discovered which result in disordered hypoxia sensing. The dominantly inherited gain-of-function HIF2α (encoded by EPAS1) gene mutation and loss-of-function PHD2 variants (encoded by the EGLN1 gene) have features of both primary and secondary polycythemia.

Secondary polycythemia

Causes include the following:

  • Physiologic Epo production - Chronic pulmonary disease, right-to-left cardiac shunts (Eisenmenger complex), hypoventilation syndromes (obstructive sleep apnea), high altitude, red cell defects
  • Epo-secreting tumors - Renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, hemangioblastoma; uterine fibroids, polycystic kidney disease
  • Hereditary - High oxygen-affinity hemoglobin variants; 2,3-diphosphoglycerate (2,3-DPG) deficiency; congenital methemoglobinemia
  • Environmental factors - Blood "doping" (autologous transfusion of red blood cells), self injection of Epo, toxins (cobalt, carbon monoxide exposure), smoking
  • Androgen excess - Functional endocrine tumor, anabolic steroids
  • Post–renal transplant

Physiologic Epo production

Secondary polycythemias are polycythemias that develop in response to Epo, whether it be an appropriate or inappropriate response. Appropriate responses to Epo are generally a result of tissue hypoxia, as related to conditions such as pulmonary disease, Eisenmenger syndrome (right-to-left shunting), high-altitude polycythemia, and the presence of hemoglobins with increased affinity for oxygen (and therefore decreased delivery of oxygen to tissues, with the resulting tissue hypoxia leading to compensatory erythrocytosis).  

Inappropriate Epo 

Inappropriate polycythemia stems from aberrant production of Epo, such as via Epo-producing tumors (hepatocellular carcinoma, renal cell carcinoma, hemangioblastoma, pheochromocytoma, uterine myomata), or from self administration of Epo.

Red blood cell enzyme deficiencies

Deficiencies of 2,3-diphosphoglycerate (2,3-DPG) result from a congenital mutation in the 2,3-BPG mutase gene. This is a rare mutation that can lead to a high-affinity hemoglobin.  

Methemoglobin reductase deficiency can lead to congenital methemoglobinemia. These patients exhibit mild polycythemia.

Polycythemia of the newborn

Polycythemia at birth is often a normal physiologic response to intrauterine hypoxic insults during labor and delivery. In addition, infant red blood cells have a high level of hemoglobin F, which is a high–oxygen-affinity hemoglobin. (See Polycythemia of the Newborn.)


Cobalt administration causes erythropoiesis by increasing HIFs. Smoking results in the formation of carboxyhemoglobin, a form of hemoglobin that cannot carry oxygen. The resulting tissue hypoxia stimulates Epo and red cell production. Carbon monoxide (CO) exposure, from engine exhaust or products of combustion, also results in preferential formation of carboxyhemoglobin and subsequent hypoxia.

Functional endocrine tumors

Excess androgens can be made from functional endocrine tumors, such as androgen-secreting tumors of the ovary or adrenal glands. Excess androgens can also be seen in conditions such as polycystic ovarian syndrome, congenital adrenal hyperplasia, and adrenal carcinoma. The erythropoietic effect of androgens comes from their ability to stimulate Epo production, as well as to induce differentiation of stem cells.

Dermoid cysts of the ovary and aldosterone-producing adenomas have been associated with elevated Epo and erythrocytosis. Hemoglobin levels return to normal after removal of these tumors. The pathophysiology associated with these lesions is not clear, but suggested mechanisms include Epo secretion, interaction between aldosterone and Epo, and mechanical compression of the renal artery.

Post–renal transplant erythrocytosis

Post–renal transplant erythrocytosis is found in 5-10% percent of renal allograft recipients. The erythrocytosis usually develops within 8-24 months after transplant and spontaneously resolves in 2 years. The pathophysiology is not well understood, but it is believed to be attributed to an increase in activity of and sensitivity to angiotensin II.[32]

Physical Examination





Diagnostic Considerations

See the list below:

  • Neonatal considerations (hematocrit >65%)
  • Normal intrauterine environment
  • Delayed cord clamping
  • Twin-twin transfusion
  • Maternal-fetal transfusion
  • Maternal smoking
  • Maternal heart disease
  • Maternal preeclampsia/eclampsia
  • Placental insufficiency
  • Maternal propranolol use
  • Intrauterine growth retardation
  • Neonatal thyroid toxicosis
  • Congenital adrenal hyperplasia
  • Trisomy 21, trisomy 13, trisomy 18
  • Hypoxemia
  • Altitude
  • Cardiac disease (right to left shunt)
  • Lung disease (chronic obstructive lung disease, sleep apnea)
  • Central hypoventilation
  • Hemoglobinopathy
  • High–oxygen affinity variety
  • Methemoglobin reductase deficiency
  • Chronic carbon monoxide exposure
  • Erythropoietin-producing tumors
  • Malignant tumor (eg, renal carcinoma, Wilms tumor, hepatomas, adrenal tumors, cerebellar hemangioblastomas)
  • Renal disease (eg, cysts, hydronephrosis, benign renal tumors)
  • Adrenal disease (eg, virilizing hyperplasia, Cushing syndrome)
  • Anabolic steroid use
  • Familial/congenital polycythemia
  • 2,3-Bisphosphoglycerate deficiency
  • Chuvash polycythemia
  • Relative erythrocytosis
  • Secondary to decreased plasma volume as with severe dehydration

Differential Diagnoses



Laboratory Studies

The following laboratory findings can be seen in polycythemia. The reference range values for the clinician's laboratory findings in polycythemia should be cross-correlated.

  • Complete blood count (CBC): Leukocytosis and thrombocytosis are commonly observed but not universal in patients with polycythemia. Leukocytes are greater than 12 X 10 9/L; platelets are greater than 400 X 10 9/L. Large platelets are often observed. Platelets can be morphologically and qualitatively abnormal. Red cell mass is greater than 36 mL/kg in men and greater than 32 mL/kg in women. RBCs often have anisocytosis, basophilic stippling, and polychromatophilia.
  • Serum erythropoietin (Epo): Elevated serum Epo levels can be used to distinguish polycythemia vera (PV) from secondary polycythemia. Elevated Epo levels are observed in secondary polycythemia. Low Epo levels suggest primary familial and congenital polycythemia (PFCP) or polycythemia vera, but Epo levels may be normal.
  • Elevated sedimentation rate
  • Spurious hyperkalemia or hypokalemia
  • Increased blood viscosity
  • Artifactual prolongation of coagulation studies

The following laboratory findings and tests can be helpful in determining the etiology of polycythemia:

  • Gene testing: Screen for EPOR mutation and JAK2 mutation if primary polycythemia is suspected
  • Molecular analysis: Consider molecular analysis of the VHL gene
  • Oxygen dissociation curves and hemoglobin electrophoresis can be used to assess for high–oxygen-affinity mutants and 2,3-disphosphoglycerate (2,3-DPG) deficiency
  • Urinalysis can reveal microscopic hematuria, a sign of renal disease
  • Elevated serum glucose and hypokalemia can suggest functioning endocrine tumors
  • Liver panel abnormalities can suggest the presence of liver disease
  • Co-oximetry should be performed in all patients in whom CO poisoning or congenital methemoglobinemia is suspected
  • P 50, or the oxygen partial pressure at which hemoglobin is 50% saturated with oxygen, is reduced in high-affinity hemoglobins

A study by Cacemiro et al indicated that compared with patients with polycythemia vera, those with secondary polycythemia have lower plasma levels of the cytokines interleukin-17A (IL-17A), interferon-γ (INF-γ), IL-12p70, and tumor necrosis factor-α (TNF-α). Consequently, the investigators suggested that the cytokine production profile of secondary polycythemia may be useful in distinguishing that disease from polycythemia vera.[33]

Imaging Studies

The following imaging studies can be helpful in determining the etiology of polycythemia:

  • Abdominal ultrasonography is helpful in excluding underlying renal and hepatic pathology
  • Chest radiographs may provide clues to pulmonary or cardiac etiologies to polycythemia
  • Computed tomography (CT) scanning of the chest, abdomen, pelvis, or head is helpful to evaluate for tumors, cancer, or other pathology

Other Tests

The need for bone marrow biopsy is still controversial. Biopsy is not a part of the diagnostic criteria. It may be helpful when trying to differentiate polycythemia vera from other myeloproliferative disorders and to assess the degree of fibrosis.

Cytogenetics are not routinely performed but should be used if the diagnosis is questionable and if the differential includes malignancy, myelodysplastic syndrome, or other myeloproliferative disorders.

Histologic Findings

If a bone marrow biopsy is performed, the marrow in polycythemia vera is typically hypercellular, including all marrow elements and displaced marrow fat. The number of megakaryocytes is usually increased with wide variation in size.  Stainable iron is decreased or absent, and, later in the disease course, fibrosis and marrow reticulin fibers are increased.[34]



Medical Care

Primary polycythemia

The goals of therapy are to maximize survival while minimizing the complications of therapy as well as of the disease itself. Phlebotomy and myelosuppressive chemotherapy are the cornerstones of therapy. Based on clinical trials in adults, these approaches have produced a median survival time of 9-14 years after the beginning of treatment. Current recommendations for treatment of young patients primarily rely on phlebotomy because the thrombosis is far less likely to occur in children and the long-term risks of leukemia over a longer life span are increased.


The goal of phlebotomy is to maintain normal red cell mass and blood volume, with a target hematocrit level of 42-46% for men and 39-42% for women. The mean survival time of adult patients treated solely with phlebotomy is 13.9 years; however, a high risk of thromboembolic complications is observed. To reduce the thrombotic risk, antiplatelet agents such as aspirin and dipyridamole were used in combination with phlebotomy. Initial studies demonstrated an increased risk of hemorrhage in the phlebotomy plus aspirin/dipyridamole arm. However, a large European study showed a decrease in thrombotic events in those patients receiving low-dose aspirin therapy and recommended aspirin therapy for those patients for whom no contraindications were noted.[35]


Hydroxyurea as a myelosuppressive agent is also widely used in high-risk patients with polycythemia vera (ie, >60 y, history of thrombosis) who require cytoreductive therapy, reducing the need for phlebotomy.[2] Neutropenia and thrombocytopenia are expected adverse effects, both of which can be rapidly corrected after holding or reducing the medication dose. The incidence of thrombotic complications is less than compared with patients treated with phlebotomy alone. However, these patients also experience higher rates of malignancy. Historically, patients have been treated with chlorambucil and busulfan. However, these patients exhibited the highest rates of secondary malignancy including acute leukemia, lymphocytic lymphomas, and skin and GI carcinomas. The rates of malignancy appear lower with busulfan than with the other alkylating agents. Currently, these agents are rarely used.

Patients treated with phosphorus-32 (32 P) tolerate treatment well and have prolonged periods of remission. However, these patients also exhibit increased rates of acute leukemias (10-15%). The mean survival time with32 P treatment is 10.9 years; therefore, phosphorous is rarely used.


Interferon-alpha is effective in eliminating JAK2V617Fexpression and inducing hematologic remission. Its use is limited by side effects, cost, and route of administration. The pegylated form and low dose treatment has decreased the rate of discontinuation of the drug secondary to side effects. In a French study, patients with polycythemia vera treated with interferon alpha showed a high rate of hematologic and molecular response.[36, 37]

Tyrosine kinase inhibitors

Imatinib is a BCR-ABL tyrosine kinase inhibitor, which has been used in some patients with polycythemia vera. It has been shown to decreased blood counts, splenomegaly, and need for phlebotomy.[38, 39, 40]

Ruxolitinib is a JAK1/JAK2 inhibitor was initially approved for primary myelofibrosis, and was used in a phase II trial of patients with PV who were refractory to hydroxyurea therapy. In this study, reduction in hematocrit, thrombocytosis, leukocytosis, and splenomegaly was seen in the ruxolitinib group.[41]

Secondary polycythemia

Phlebotomy is used for symptomatic hyperviscosity. The goal is to treat the underlying cause of polycythemia.

Surgical Care

Surgery is not typically indicated. Occasionally, splenectomy is performed late in the course of the disease if massive splenomegaly causes adverse effects such as early satiety, anemia, or thrombocytopenia from sequestration. Please note that these patients have a high risk of complications during surgical procedures.


Consult a neurologist and neurosurgeon if evidence of a stroke is present.


Diet is unrestricted.


Contact sports and other activities should be limited for individuals in hypercoagulable and hypocoagulable states.



Medication Summary

Current recommendations for treatment of young patients with polycythemia primarily rely on phlebotomy.

Antineoplastic agents

Class Summary

The following medications are not approved for pediatric polycythemia but are extrapolated from other pediatric treatment regimens, including leukemia and myelodysplastic syndrome.

Interferon alfa 2a and 2b (Roferon-A [alfa-2a], Intron A [alfa-2b])

A recombinant purified protein used IV for CML, hairy cell leukemia, and Kaposi sarcoma. Inhibits cellular growth and alters cell differentiation.

Chlorambucil (Leukeran)

Antineoplastic alkylating agent of nitrogen mustard type used for CLL, giant follicular lymphoma, Hodgkin lymphoma, and lymphosarcoma.

Hydroxyurea (Hydrea)

Inhibitor of deoxynucleotide synthesis. PO antineoplastic agent used in CML, melanoma, ovarian carcinoma, and some head and neck carcinomas.

Busulfan (Myleran)

Potent cytotoxic drug that, at recommended dosage, causes profound myelosuppression. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.




The following are complications of polycythemia:

  • Vascular occlusive events - Splenic infarcts, thrombosis (cerebral, portal vein, pulmonary embolus)

  • Hemorrhage

  • Marrow fibrosis resulting in pancytopenia

  • Malignancy - Acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), lymphoma

  • Hyperuricemia - Renal stones, nephropathy, gout

  • Budd-Chiari syndrome


The median survival time for patients with polycythemia vera is 18 months for untreated patients and 9-14 years for treated patients.

Patient Education

Inform patients that they are prone to surgical complications and are at high risk in trauma situations secondary to coagulopathies.